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CNSCNS
CNS• Normal
–Neurons
–Glia• Astrocytes
• Oligodendrocytes
• Ependymal Cells
• Microglia
• Pathology (13 Questions)
Classical Disease Patterns
• Degenerative
• Inflammatory
• Neoplastic
Classical CNS Disease Patterns
• Degenerative
• Inflammatory
• Neoplastic
• Traumatic
• 1) What are general patterns of CNS cell pathology?
• 2) What are the consequences of ↓↑ CNS pressure?
• 3) What are common patterns of CNS malformations?• 4) What are common perinatal CNS injuries?• 5) What are the patterns of CNS trauma?• 6) What are the patterns of CNS vascular disease?• 7) What are the patterns of CNS infection?
___________________________________________________• 8) What are the patterns of CNS prion disease?• 9) What are the patterns of CNS demyelinating disease?• 10) What are the patterns of CNS degenerative disease?• 11) What are the CNS genetic metabolic diseases?• 12) What are the CNS acquired metabolic/toxic diseases?• 13) What are the CNS tumors?
CELLULAR REACTIONS• Neurons
– Acute (RED neuron, karyolysis)– Subacute, chronic, cell loss, gliosis– Axonal– Inclusions (lipid, prot., carb., viruses)
• Glia, “gliosis”– Swelling– Fibers– Inclusions
ACUTE NEURONAL INJURY
“RED” NEURONS
CEREBRAL EDEMA(normal weight 1200-1300 grams)
• Vasogenic (disrupted BBB)Intravascular INTER-cellular
• Cytotoxic INTRA-cellular
CEREBRAL EDEMA• Subfalcine (SUPRA-tentorial)
• Cingulate (TENTORIAL)
• Cerebellar tonsilar (SUB-tentorial, or INFRA-tentorial)
• DDX:–EVERYTHING
• SYMPTOMS–HEADACHE
–HALLUCINATIONS
–COMA
–DEATH
CEREBRAL EDEMA
HYDROCEPHALUS
HYDROCEPHALUS• Impaired RESORPTION• Increased PRODUCTION
• OBSTRUCTION• COMMUNICATING (entire)• NON-COMMUNICATING (part)• HIGH Pressure• NORMAL Pressure
CNS MALFORMATIONS• Neural Tube
– Anencephaly, Encephalocele, Spina Bifida
• Forebrain– Polymicrogyria, Holoprosencephaly, Agenesis of
Corpus Callosum
• Posterior Fossa (Infratentorial)– Arnold Chiari (infratentorial herniation), Dandy-
Walker (cerebellar cyst)
• Syringomyelia/Hydromyelia
SPINA
BIFIDA
POLYMICROGYRIA
HOLOPROSENCEPHALY
SYRINGOMYELIA
(note “SYRINX”)
PERINATAL Brain Injuries• Intraparenchymal Hemorrhage• Intraventricular hemorrhage (premies)• Periventricular “leukomalacia” (i.e.,
infarcts)
• Cerebral “Palsy” refers to nonprogressive diffuse cerebral pathology apparent at childbirth
CNS TRAUMA• Skull Fractures
• Parenchymal Injuries
• Traumatic Vascular Injury
• Sequelae
• Spinal Cord Trauma
BRAIN TRAUMA• Contusion (bruise)
• Laceration (tear)
• Coup/Contre-Coup
• Concussion
“HAIRLINE” “DEPRESSED”, aka
“DISPLACED”
HEMATOMAS/HEMORRHAGE
• EPIDURAL (fx)• SUBDURAL (trauma NO fx)• SUBARACHNOID (arterial, no trauma)• INTRAPARENCHYMAL (any)• INTRAVENTRICULAR (no trauma, rare
in adults, common in premies)
EPIDURAL HEMATOMA
SUBDURAL HEMATOMA
SUBARACHNOID
INTRAPARENCHYMAL
INTRAPARENCHYMAL
INTRAVENTRICULAR
CNS TRAUMA SEQUELAE
• Hydrocephalus (WHY?)
• Dementia (Punch Drunk Syndrome)
• Diffuse Axonal Injury (white matter)
SPINAL CORD TRAUMA• Parallels BRAIN patterns of
injury on a cellular basis• Usually secondary to spinal
column displacement• Level of injury mirrors motor
loss: Death Quadriplegia Paraplegia
Cerebrovascular Diseases (CVA, “Stroke”)
• Ischemic (Thrombotic) (↓ blood and 02)– Global– Focal (regional):
– ACUTE: edema neuronal microvacuolization pyknosis karyorrhexis neutrophils
– CHRONIC: macrophages gliosis
• Hemorrhagic (rupture of artery/aneurysm)
THROMBOTIC
MCA
HEMORRHAGIC
ACA
A) EDEMA
B) “RED” NEURONS
C) POLYs
D) MONO’s (MACs)
E) GLIOSIS
Histopathologic progression of CNS infarcts
HYPERTENSIVE CVA• Intracerebral
• Basal Ganglia Region (lenticulostriate arteries of internal
capsule, putamen)
HYPERTENSIVE CVA
LACUNAR INFARCTS
“SLIT” HEMORRHAGE(s)
SUBARACHNOIDHEMORRHAGE
• Rupture of large intracerebral arteries which are the primary branches of the anatomical circle (of Willis)
• Congenital (“berry” aneurysms)• Atherosclerotic (atherosclerotic
aneurysms, or direct wall rupture)
HYPERTENSIVEENCEPHALOPATHY
• ACUTE– Headaches– Confusion– Anxiety– Convulsions
• CHRONIC– Dementia (MID, Multi-Infarct-Dementia)– Gait Disturbances– Basal Ganglia symptoms
CNS INFECTIONS• ACUTE MENINGITIS
• ACUTE FOCAL SUPPURATIVE
• CHRONIC BACTERIAL
• VIRAL
• FUNGAL
• OTHER
INFECTIONS• Meningitis (generally* bacterial)
– E. coli, Strep B (neonates)– H. influenzae (children)– Neisseria meningitidis (adults)– Strep. pneumoniae, Listeria (elderly)– PMNs in CSF, INCREASED protein, REDUCED glucose
• Encephalitis (generally viral)– Arboviruses, HSV, CMV, V/Z, polio, rabies, HIV– Lymphs and macrophages in perivascular “Virchow-
Robbins” spaces
• Meningoencephalitis* viral, chemical, tumoral
ACUTE FOCAL SUPPURATIVECNS INFECTIONS
• CEREBRAL ABSCESSES– Local (mastoiditis, sinusitis)– Hematogenous (tooth extraction, sepsis)– Staph, Strep– Often fibrous capsule, liquid center
• SUBDURAL EMPYEMA (IN SINUSITIS)
• EXTRADURAL ABSCESS (IN OSTEOMYELITIS)
SUBDURAL EMPYEMA
CHRONIC BACTERIALMeningo-encephalits
• TB, brain and meninges
• SYPHILIS, gummas in brain
• LYME DISEASE (Neuro-Borreliosis)
TUBERCULOMA
VIRALMeningo-encephalitis
• ARBO VIRUSES (West Nile, Equines, Venez., many more)• HSV1• HSV2• V/Z• CMV• POLIO• RABIES• HIV• Progressive Multifocal Leukoencephalopathy (JC)• Subacute Sclerosing Panencephalitis (Measles)
VIRAL
ENCEPHALITIS
PERIVASCULAR
LYMPHOCYTIC
“CUFFING”
Bitemporal encephalitis is HSV until proven otherwise!
HSV = TEMPORAL lobe(s)
PERIVASCULAR
GIANT CELLS
in WHITE MATTER in
HIV
ENCEPHALITIS
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
• JC Polyoma virus is the cause (JCV)
• Primarilly affects oligodendocytes
• Ergo, demyelination is the main feature
PML
SUBACUTE SCLEROSINGPANENCEPHALITIS (SSPE)• VERY rare since measles eradicated
• Thought to be caused by measles virus
FUNGALMENINGO-ENCEPHALITIS
•CRYPTOCOCCUS•CANDIDA• ASPERGILLIS• MUCOR
(Mostly in immunocompromised hosts)
CRYPTOCOCCUS
MICROABSCESSES
OTHERS• MALARIA
• TOXOPLASMOSIS (in HIV)
• AMEBIASIS
• TRYPANOSOMES
• RICKETTSIAE
• ECHINOCOCCUS
CNS IICNS II
• 1) What are general patterns of CNS cell pathology?
• 2) What are the consequences of ↓↑ CSF pressure?
• 3) What are common patterns of CNS malformations?
• 4) What are common perinatal CNS injuries?
• 5) What are the patterns of CNS trauma?
• 6) What are the patterns of CNS vascular diseases?
• 7) What are the patterns of CNS infection?
• 8) What are the patterns of CNS prion diseases?
• 9) What are the patterns of CNS demyelinating diseases?
• 10) What are the patterns of CNS degenerative diseases?
• 11) What are the CNS genetic metabolic diseases?
• 12) What are the CNS acquired metabolic/toxic diseases?
• 13) What are the CNS tumors?
PRION DISEASES• Creutzfeldt-Jakob Disease (CJD)• Gerstmann-Straussler-Scheinker syn. (GSS)
• Fatal familial insomnia
• Kuru, human variety (cannibalism)
• Scrapie (sheep and goats)
• Mink transmissible encephalopathy
• Chronic wasting disease (deer and elk)
• Bovine Spongiform Encephalopathy (BSE)
PRION DISEASES:common features
• Infectious agents with apparently no DNA
• DEMENTIA
• Prion Protein (PrP) accumulation
• “SPONGIFORM” changes in neurons and glia
• TRANSMISSIBLE, FATAL, NO Rx
PRION PROTEINNormally found in humans
Exact structure known, 208 amino acids
Specific chromosome, #20, specific genes also known
Requires a
conformational change to accumulate and do damage
CJD (Creutzfeldt-Jakob)• 1 per million incidence, 7th decade
• Sporadic cases, not epidemic
• Transmitted!
• Familial cases well documented
• Rapidly progressive dementia
• Grey Matter
• Cerebellar ataxia also, usually
• FATAL, no treatment known, like ALL prion diseases
DEMYELINATING DISEASES• MS (MULTIPLE SCLEROSIS)• MS variants
• ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)
• ACUTE NECROTIZING HEMORRHAGIC ENCEPHALOMYELITIS (ANHE)
• Many, many, many others. Remember:
DEMYELINATION is a NON-SPECIFIC reaction to MANY types of CNS injury, and demyelination also causes edema
MS• Cause: ?• USA prevalence: 1:1000 • F>>M, Ages: 30’s, 40’s• Immune response primarily against CNS myelin
(white matter)• Regional area of white matter demyelination is
called “PLAQUE”• Increased CSF gamma globulin, i.e., oligoclonal
bands• Often presents with VISUAL problems• EXACERBATIONS/REMISSIONS
PLAQUES, MS
CNS DEGENERATIVE DISEASES
• CORTEX (dementias)
• BASAL GANGLIA and BRAIN STEM (parkinsonian)
• SPINOCEREBELLAR (ataxias)
• MOTOR NEURONS (muscle atrophy)
CNS DEGENERATIVE DISEASES
• CORTEX (dementias)–ALZHEIMER DISEASE– Frontotemporal
– Pick Disease (also primarily frontal)
–Progressive Supranuclear Palsy (PSP)
–CorticoBasal Degeneration (CBD)
– Vascular Dementias (MID)
ALZHEIMER DISEASE• Commonest cause of dementias (majority)
• Sporadic, 5-10% familial
• CORTICAL (grey matter) ATROPHY• NEURITIC PLAQUES*
(extraneuronal)
• NEUROFIBRILLARY TANGLES (intraneuronal)
• AMYLOID!!! (i.e., “BETA” amyloid)
Neuritic plaques Neuritic plaques, stained with
anti- beta amyloid immunostain
OTHER CORTICAL DEMENTIAS(tau gene/protein, tau-opathies)
• FRONTOTEMPORAL
• PICK DISEASE (LOBAR ATROPHY)
• PROGRESSIVE SUPRANUCLEAR PALSY (PSP)
• CORTICOBASAL DEGENERATION (CBD)
• VASCULAR DEMENTIA (MID)
VASCULAR DEMENTIA• Associated with multiple infarcts,
hence the name MID (Multiple Infarct Dementia)– Lacunar infarcts– Cortical microinfarcts– Multiple embolic infarcts
• SECOND commonest form of dementia after Alzheimer
CNS DEGENERATIVE DISEASES
• BASAL GANGLIA and BRAIN STEM
–Parkinsonism–Parkinson Disease
–Multiple System Atrophy
–Huntington Disease
Parkinsonism• Is a clinical “syndrome”, NOT a disease
– Diminished facial expression – Stooped posture– Slowness of voluntary movement– “Festinating” gate (short, fast)– Rigidity (cogwheel)– “Pillrolling” tremor
• The above clinical findings involve pathology of the SUBSTANTIA NIGRA, and include:–PARKINSON DISEASE– MULTIPLE SYSTEM ATROPHY– POSTENCEPHALIC PARKINSONISM– Progr. Supranuc. Palsy, Cort. Basal Degen.
(cortical disorders)
PARKINSON DISEASE
•PALLOR of the SUBSTANTIA NIGRA (and LOCUS COERULEUS)
• LEWY BODIES (alpha-synuclein protein)
LOCUS COERULEUS* in PONS
(CERULEUS**)* 254,000 ** 76,000
PARKINSON DISEASE• Parkinsonism symptoms, i.e.,
– cogwheel rigidity– intention tremor
• Progressive• Hallucinations• Dementia• Symptomatic response to L-DOPA
MULTIPLE SYSTEM ATROPHY
• MSA• WIDE SPECTRUM of diseases• GLIAL CYTOPLASMIC
INCLUSIONS (GCIs) in oligodendrocytes (alpha synuclein)
• Clinically,– parkinsonism symptoms – autonomic dysfunction
HUNTINGTON DISEASE• Classical familial,
genetic disease• Progressive motor
loss and dementia• “chorea”, i.e.
“jerky” movements• Progressive, fatal• Atrophy of basal
ganglia, i.e., corpus striatum
Cortical (basal ganglia) atrophy
Ventricular enlargement
CNS DEGENERATIVE DISEASES
• SPINOCEREBELLAR DEGENERATIONS (ATAXIAS)–Spinocerebellar ataxias
–Friedrich Ataxia
–Ataxia-Telangiectasia
SPINOCEREBELLAR DEGENERATIONS
• Cerebellar cortex• Spinal cord• Peripheral nerves
• FEATURES:
–ATAXIA (loss of extremity muscle coordination)
– SPASTICITY– NEUROPATHIES
CNS DEGENERATIVE DISEASES
• MOTOR NEURONS
–ALS (Amyotrophic Lateral Sclerosis, i.e., Lou Gehrig’s disease)
– BulboSpinal Atrophy (Kennedy Syndrome)
– Spinal Muscular Atrophy
Amyotrophic Lateral Sclerosis
• Unknown etiology
• Progressive muscle atrophy due to motor neuron loss (lower, upper)
• 5-10% familial
• Lou Gehrig had it, so does Steven Hawking
• Hand weakness diaphragm
• Anterior horn cells reduced and gliotic
A.L.S., DEMYELINATION IN CORTICOSPINAL
TRACTS
ALS, pathologic changes in anterior horn cells
GENETIC METABOLIC DISEASES
• NEURONAL STORAGE DISEASES– (classical autosomal recessive enzyme deficiencies)
• “LEUKO”-DYSTROPHIES– (abnormal “myelin” synthesis)
• MITOCHONDRIAL ENCEPHALOPATHIES– (mitochondrial gene mutations)
LEUKODYSTROPHIES• Krabbe
• Metachromatic-
• Adreno-
• Pelizaeus-Merzbacher
• Canavan
ACQUIRED TOXIC/METABOLICCNS DISEASES
• Vitamin B1 deficiency (Wernicke-Korsakoff)
• Vitamin B12 deficiency (vibratory sense)
• Diabetes Increased/Decreased GLUCOSE
• Hepatic Failure (NH4+)
• CO (Cortex, hippocampus, Purkinje cells)
• CH3-OH, Methanol (Retinal ganglion cells)
• CH3-CH2-OH (acute/chronic, direct/nutrit’l)
• Radiation (Brain MOST resistant to Rad. Rx.)
• Chemo (Methotrexate + Radiation)
128 Hz
CNS TUMORS• GLIOMAS (do not metastasize out of the
CNS)– Astrocytes (I, II, III, IV)– Oligodendroglioma– Ependymoma
• NEURONAL (neuroblastoma)
• POORLY DIFFERENTIATED (medulloblastoma)
• MENINGIOMAS• LYMPHOMAS• METASTATIC
CNS TUMORS• SYMPTOMS?
– Headache– Vomiting– Mental Changes– Motor Problems– Seizures– Increased Intracranial Pressure
–ANY localizing CNS abnormality
CNS TUMORS• History• Physical• Neurologic exam• LP (including cytology)• CT• MRI• Brain angiography• Biopsy
CNS TUMORS• Benign? Malignant?, Primary vs. met?• Location?• Age?• X-ray Density? MRI signals?• Calcifications?• Vascularity?• Necrosis? • Liquefaction?• Edema?• Compression of neighbors?
GLIOSIS vs. GLIOMA• Age?• White vs. Grey Matter?• Gross texture?• Vascularity?• Mitoses? • (N/C, Pleomorphism, Hyperchromasia)• Calcifications?• Cysts?• Satellitosis?• Delineation?
NON ASTROCYTIC
GLIOMAS
OLIGODENDROGLIOMAOccurs frequently in the frontal or temporal lobes
Can be classified as low grade or high grade
Common among men and women in their 20s-40s, but can occur in children
More common in men than women
Accounts for two percent of all brain tumors
May be associated with 1p or 19q chromosomal losses
EPPENDYMOMAUsually localized to one area of the brain
Develops from cells that line the hollow cavities at the bottom of the brain and the canal containing the spinal cord
Can be slow growing or fast growing
May be located in the ventricles (cavities in the center of the brain)
May block the ventricles, causing hydrocephalus (water on the brain)
Sometimes extends to the spinal cordCommon in children, and among men and women in their 40s and 50s
Occurrence peaks at age five and again at age 34
Accounts for two percent of all brain tumors
ZoomMe!
MENINGIOMAS• Occur where dura is• Very vascular• BENIGN, but………….(can be damned invasive)• Can invade skull, etc.• Only invade (displace) brain in areas adjacent to
dura, i.e., parasagittal, falx, tentorium, venous sinuses
• Small, firm, and well defined like a SUPERBALL
• Often (usually?) have PSAMMOMA bodies
HIV
METASTATIC CNS TUMORS
•LUNG• BREAST• MELANOMA• KIDNEY• GI
“PARA”NEOPLASTIC SYNDROMES
•SMALL CELL, LUNG
• LYMPHOMAS• BREAST CA
• Purkinje Cell Degeneration
• Encephalitis, Limbic System
• Sensory Neuron Degeneration, DRG
• Eye Movement Disorders
FAMILIAL TUMOR SYNDROMES• NF1
– Neurofibromas
– Gliomas
• NF2– Schwannomas
– Meningiomas
• Tuberous Sclerosis, i.e., CNS and somatic “hamartomas”
• Von-Hippel-Lindau, CNS hemangioblastomas, chiefly cerebellar